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Peroxisome proliferator-activated receptor α activates cyclooxygenase-2 gene transcription through bile acid transport in human colorectal cancer cell lines

  • Hiroshi Oshio
  • Takaaki Abe
  • Tohru Onogawa
  • Hideo Ohtsuka
  • Takeaki Sato
  • Takayuki Ii
  • Kouji Fukase
  • Mitsuhisa Muto
  • Yu Katayose
  • Masaya Oikawa
  • Toshiki Rikiyama
  • Shinichi Egawa
  • Michiaki Unno
Liver, Pancreas, and Biliary Tract

Abstract

Background

Evidence is accumulating that bile acids are involved in colon cancer development, but their molecular mechanisms remain unexplored. Bile acid has been reported to be associated with induction of the cyclooxygenase-2 (COX-2) gene. Because the human liver-specific organic anion transporter-2 (LST-2/OATP8/OATP1B3) is expressed in gastrointestinal cancers and might transport bile acids to the intracellular space, we studied the molecular mechanisms by which bile acids induce the transcription of COX-2, and the role of LST-2 in colonic cell lines.

Methods

Transcriptional activity of COX-2 was measured using a human COX-2 promoter-luciferase assay under various concentrations of bile acids. Electrophoresis mobility shift assays (EMSAs) for peroxisome proliferators-activated receptor (PPAR) α and cyclic AMP responsive element (CRE) were performed.

Results

The COX-2 promoter was induced by lithocholic acid (LCA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA). Deletion and site-directed mutation analyses showed that CRE is the responsive element for LCA. An adenovirus expression system revealed that LST-2 is responsible for induction of COX-2. By EMSA using oligonucleotides of CRE, we observed formation of a specific protein-DNA complex, which was inhibited by a specific antibody against PPARα and CRE. A PPARα-specific agonist induced transcription of COX-2.

Conclusion

These results indicate that COX-2 is transcriptionally activated by the addition of LCA, CDCA, and DCA and that LST-2 plays an important role by transporting bile acid to the intracellular space. Moreover, LCA-dependent COX-2 gene activation consists of a transcriptional complex including PPARα and CRE-binding protein. Thus, this induction of COX-2 may participate in carcinogenesis and progression of colorectal cancer cells.

Key words

LST-2 OATP1B3 COX-2 PPARα bile acid 

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Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Hiroshi Oshio
    • 1
  • Takaaki Abe
    • 2
    • 3
  • Tohru Onogawa
    • 1
  • Hideo Ohtsuka
    • 1
  • Takeaki Sato
    • 1
  • Takayuki Ii
    • 1
  • Kouji Fukase
    • 1
  • Mitsuhisa Muto
    • 1
  • Yu Katayose
    • 1
  • Masaya Oikawa
    • 1
  • Toshiki Rikiyama
    • 1
  • Shinichi Egawa
    • 1
  • Michiaki Unno
    • 1
  1. 1.Division of Gastroenterological Surgery, Department of SurgeryTohoku University Graduate School of Medical ScienceSendaiJapan
  2. 2.Division of Nephrology, Endocrinology, and Vascular Medicine, Department of MedicineTohoku University Graduate School of Medical ScienceSendaiJapan
  3. 3.PRESTOJapan Science and Technology Corporation (JST)TokyoJapan

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